Identical twins provide clues for potential CVID treatment

“Communication problems” that result from defects in types of immune cells including B cells impair immune response and may play a role in common variable immunodeficiency, according to a study published in Nature Communications.

The researchers found these problems by generating single-cell data taken from healthy individuals and from patients with common variable immunodeficiency (CVID). These participants included a pair of identical twins — one who was healthy and one with CVID.

The sibling with CVID had fewer B cells. Also, defects in these B cells led to epigenetic problems with DNA methylation, chromatin accessibility and transcriptional defects in memory B cells. There were defects in the cell-to-cell communication that the immune system requires for normal function as well.

An examination of the study’s wider CVID cohort revealed similar problems, giving the researchers a model for characterizing the disease that could potentially be used to develop new treatments.

Healio spoke with Javier Rodríguez-Ubreva, PhD, senior researcher, and Esteban Ballestar, PhD, group leader, both of the Josep Carreras Leukaemia Research Institute, to find out more about their study and its implications for CVID care.

Healio: What prompted the study?

Rodríguez-Ubreva and Ballestar: CVID is a rare disease that currently has no cure. Patients with this immunodeficiency have several clinical complications that seriously affect their quality of life.

CVID pathogenesis remains largely unexplained, given that only 20% of CVID cases

can be accounted for by genetic defects. The study of samples derived from twins discordant for CVID, who are genetically identical but only one in the pair displaying alterations in the immune system, allows the analysis of epigenetic alterations that may contribute to the development of the disease.

Healio: How do these differences manifest in twins?

Rodríguez-Ubreva and Ballestar: Despite the heterogeneity of CVID, the main difference between twins is their differential propensity to effectively respond against infections. Usually, the twin displaying CVID suffers recurrent respiratory infections and requires immunoglobulin supplementation.

Healio: What impact does environment have on creating or exacerbating these differences between twins?

Rodríguez-Ubreva and Ballestar: It is likely that the exposure to different environments at prenatal or post-delivery time, or even their differential early infection history, may have induced epigenetic alterations that ultimately lead to a difference in gene expression and twin discordance in CVID.

Healio: What led your team to focus on B cells as a potential driver behind CVID?

Rodríguez-Ubreva and Ballestar: Patients with CVID are characterized by low serum immunoglobulin concentrations, defective specific antibody production and increased susceptibility to bacterial infections of the respiratory and gastrointestinal tracts. In this study, we focused our analyses on naive and memory B cells, whose activation is directly involved in the defective production of immunoglobulins observed in these patients.

CVID has been traditionally seen as a B-cell disorder. However, nowadays CVID is viewed with a more general perspective. Although we have mainly focused on B cells, the single cell atlas that we have generated represents a resource that others can use to study other immune cell types that are altered in CVID.

Healio: Would you expect these impairments in B cells to be behind CVID or other immune disorders in other patients?

Rodríguez-Ubreva and Ballestar: In this study, we have found common molecular alterations in different patients with CVID. However, we have also identified that the extent of such alterations differs among the different CVID subtypes. It is likely that some of the genes that are altered in CVID are also altered in other disorders and, in these regards, it is very important to extend this study to other immunodeficiencies

Healio: Were there any other particularly surprising or significant differences or results?

Rodríguez-Ubreva and Ballestar: Our results suggest that the defects in the proper function of B cells might be caused not only by intrinsic defects within the B cells, but also by alterations in other immune cells that actively interact and communicate with B cells during the immune response.

Healio: How can these findings be used in potential treatment?

Rodríguez-Ubreva and Ballestar: We have identified several cellular pathways that are altered and could be targeted with existing drugs. More research expanding the number of patients will be needed to consider complementary or alternative therapeutic options.

Healio: What is the next step in this research?

Rodríguez-Ubreva and Ballestar: Our study provides the first atlas of CVID. However, as indicated, this is a heterogeneous clinical entity, and it is critical to expand these studies by incorporating more patients and having different subtypes. This information could be useful to better characterize patients and give additional clues on which pathways are good candidates to explore novel therapeutic options. In this sense, close collaboration with clinical groups, expert in immunodeficiencies, is essential.

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